Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof

ABSTRACT

The invention pertains to the use of compounds represented by the formula, Q-G 1 -G 2 -G 3 -G 4 -Z, where Q is 
     
       
         
         
             
             
         
       
     
     The compounds can be used as diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also can be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation U.S. application Ser. No. 14/628,373,filed Feb. 23, 2015, now U.S. Pat. No. 9,340,566, which is a divisionalof U.S. application Ser. No. 13/458,452, filed Apr. 27, 2012, now U.S.Pat. No. 8,962,618, which is a continuation of U.S. application Ser. No.13/256,952, filed Sep. 16, 2011, now abandoned, which is the U.S.national stage application of International Patent Application No.PCT/US2010/027889, filed Mar. 19, 2010, which claims the benefit of U.S.Provisional Application Ser. No. 61/162,170, filed Mar. 20, 2009, thedisclosures of which are hereby incorporated by reference in theirentireties, including all figures, tables and amino acid or nucleic acidsequences.

BACKGROUND

Obesity is a chronic disease that has reached global epidemicproportions with over 1 billion adults being overweight (BMI 25-29.9) orobese (BMI>30). In the U.S.A. alone, the number of adults who are eitheroverweight or obese is estimated to be over 150 million and is still onthe rise. Currently marketed therapies (orlistat, sibutramine) havedemonstrated sub-optimal efficacy (only 5-10% weight loss when used incombination with diet and exercise plans) and/or poor tolerabilityprofiles. More recently, Sanofi Aventis' CB 1 receptor antagonist,rimonabant, was withdrawn from the market due to adverse psychiatricside effects. The success of future obesity treatments will depend ontheir ability to elicit sustained and robust weight loss with improvedsafety/tolerability profiles.

Obesity (BMI>30) is the long term consequence of an imbalance betweenenergy intake and energy expenditure (Hill et al., 2000). Further,obesity is associated with decreased life span due to numerousco-morbidities that include coronary artery disease, hypertension,stroke, diabetes, hyperlipidemia, osteoarthritis and some cancers.Adiposity is a hallmark of obesity that results from the excessivedeposition of the energy storage molecule triacylglycerol (TAG) in alltissues as well as an increase in overall adipose tissue mass due toincreased adipocyte size and number. Increases in intracellular TAGand/or TAG precursors in non-adipocyte cell types, adipocyte invasion ofnon-adipose tissues, and increase in adipose mass are the causativefactors of co-morbidities associated with obesity (Van Herpen et al.,2008). Recent studies suggest that the inhibition of diacylglycerolO-acyltransferase 1 (DGAT-1) may be an effective strategy to treatobesity and obesity associated co-morbidities (Chen et al., 2005; Shi etal., 2004).

DGATs are membrane-bound enzymes that catalyze the terminal step of TAGbiosynthesis (Yen et al., 2008). Two enzymes, which catalyze theacylation of diacylglycerol (DAG) to form TAG, have been identified andare designated DGAT-1 and DGAT-2. Importantly, the DGAT-1 and DGAT-2enzymes have no significant protein sequence homology. In addition tocatalyzing the acylation of DAG to form TAG, DGAT-1 has also been shownto catalyze the acylation of monoacylglycerol to form DAG (Yen et al.,2005). DGAT-1 and DGAT-2 null mice have been generated and extensivelycharacterized (Smith et al., 2000; Stone et al., 2004). In detail,DGAT-2 null mice are lipopenic and die soon after birth from reductionsin substrates for energy metabolism and from impaired permeabilitybarrier function. In contrast, DGAT-1 mice are fertile and viable with anormal life span and do not become obese when fed a TAG rich diet.DGAT-1 null mice exhibit both reduced postprandial plasma TAG levels andincreased energy expenditure, but have normal levels of circulating freefatty acids. Conversely, transgenic mice that over-express DGAT-1 inadipose tissue are predisposed to obesity when fed a TAG rich diet andhave elevated levels of circulating free fatty acids (Chen et al.,2002).

In humans, DGAT-1 is highly expressed in several tissue types that arerelevant to obesity, such as intestine, liver and adipose (Yen et al.,2008). Further, DGAT-1 is predominantly localized to the lumen of theendoplasmic reticulum (Yamazaki et al., 2005). Thus, there are severalsites of action for a DGAT-1 inhibitor that can lead to both a reductionin adiposity and body weight. First, blocking DGAT-1 activity in theintestine or liver will inhibit the export of chylomicron and VLDLparticles, respectively, thereby reducing peripheral TAG deposition thatoriginates either from dietary TAG re-esterification or from de novolipogenesis. Second, blocking DGAT-1 activity in adipose tissue willdecrease both adipocyte size and number. In both cases, non-esterifiedfatty acids will be mobilized for use as an energy source rather thanused for storage. DGAT-1 inhibition may also generate a peripheralsatiety signal resulting in an anorexigenic effect. The phenotype of theDGAT-1 null mice, coupled with DGAT-1's role in human whole body TAGhomeostasis, provides a compelling rationale for the investigation ofDGAT-1, as a target for the treatment of obesity. Recently, the in vivopharmacology of a potent orally bioavailable DGAT-1 inhibitor wasdisclosed (Zhao et al., 2008). Proof of concept studies in rodent modelsof obesity with this inhibitor demonstrated target engagement, weightloss and reductions in adiposity. This inhibitor showed high oralbioavailability and high systemic exposure.

High systemic exposure of a DGAT-1 inhibitor can potentially result inundesirable side effects such as reduced lactation in nursing females,reduced sebum production, and exacerbation of myocardial injury duringischemia. In detail, human milk TAGs are a major source of nutrition tothe nursing infant and systemic inhibition of DGAT-1 would reduce milkTAG production. Female DGAT-1 null mice are unable to nurse their pupsdue to reduced lactation. Triglycerides are also a major component ofhuman sebum, which is an important skin lubricant. Systemic inhibitionof DGAT-1 would reduce sebum production and may result in skin and hairdisorders as observed in DGAT-1 null mice. Finally, the systemicinhibition of DGAT-1 could substantially increase free fatty acidavailability and utilization by the heart. During ischemia, theutilization of a less efficient fuel source such as fatty acids ratherthan glucose may enhance myocardial injury.

One approach to improve the therapeutic index of DGAT-1 inhibitors is toexclusively target DGAT-1 expressed in the enterocyte by restrictingdrug exposure primarily to enterocytes. DGAT-1 inhibitors with lowsystemic exposure and good oral bioavailability specifically targeted toenterocytes would avoid safety issues potentially associated withcompounds that reach high levels in the systemic circulation.

SUMMARY OF THE INVENTION

The invention pertains to use of DGAT-1 inhibitors to treat and/orprevent overweight, obesity and the dyslipidemia associated with it.Because of the mechanism and specific targeting to enterocytes of theDGAT-1 inhibitors of the invention, other conditions also can beameliorated, reduced or avoided. These conditions include highpostprandial triglycerides (very common in diabetes) or diet- orobesity-related hypertriglyceridemia, cardiovascular risk associatedwith excessive triglycerides, and insulin resistance and glucoseintolerance (e.g., improved insulin sensitivity due to reduceddeposition of liver and skeletal muscle fat) seen in overweightpatients, those with diabetes or other glucose metabolic disorders suchas Syndrome X, polycystic ovary or other disorders.

The DGAT-1 inhibitor compounds and compositions disclosed hereinprimarily target enterocytes lining the intestinal walls. Thus, thedisclosed compounds can be administered orally and are taken up readilyinto enterocytes; however, compounds of the invention are not readilyexported from the enterocytes into the systemic circulation. Thisresults in low systemic exposure to the compounds disclosed herein andreduced risk of systemic side effects associated with general systemicDGAT-1 inhibition.

DETAILED DESCRIPTION DEFINITIONS

For a variable that occurs more than one time in any substituent, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Combinations of substituents are permissible only ifsuch combinations result in stable compounds. Stable compounds arecompounds, which can be isolated in a useful degree of purity from areaction mixture. Additionally, as used in the specification and theappended claims, unless specified to the contrary, the following termshave the meaning indicated below.

The term “alkyl” refers to a straight or branched or cyclic chainhydrocarbon radical with only single carbon-carbon bonds. Representativeexamples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, andcyclohexyl, all of which may be optionally substituted. Alkyl groups areC₁-C₁₂ and include alkyl groups that are C₁-C₈ in some embodiments.

The term “aryl” refers to aromatic groups which have 5-14 ring atoms andat least one ring having a conjugated pi electron system and includescarbocyclic aryl, heterocyclic aryl and biaryl groups, all of which maybe optionally substituted.

Carbocyclic aryl groups are groups which have, in various embodiments,6-10 or 6-14 ring atoms wherein the ring atoms on the aromatic ring arecarbon atoms. Carbocyclic aryl groups include monocyclic carbocyclicaryl groups and polycyclic or fused compounds such as optionallysubstituted naphthyl groups.

Heterocyclic aryl or heteroaryl groups are groups which have, in variousembodiments, 5-10 or 5-14 ring atoms wherein 1 to 4 heteroatoms are ringatoms in the aromatic ring and the remainder of the ring atoms beingcarbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, andselenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl,pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl,imidazolyl, and the like, all optionally substituted.

The term “biaryl” represents aryl groups which have 5-14 atomscontaining more than one aromatic ring including both fused ring systemsand aryl groups substituted with other aryl groups. Such groups may beoptionally substituted. Suitable biaryl groups include naphthyl andbiphenyl.

The term “optionally substituted” or “substituted” includes groupssubstituted by one to six substituents, independently selected fromlower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lowerheterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy,aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl,lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, loweracylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, loweracyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, loweralkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino,sulfonyl, lower-carboxamidoalkylaryl, lower-carboxamidoaryl, lowerhydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy-, loweraminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl,and lower arylalkyloxyalkyl.

“Substituted aryl” and “substituted heteroaryl” refers to aryl andheteroaryl groups substituted with 1-3 substituents. These substituentsare selected from the group consisting of lower alkyl, lower alkoxy,lower perhaloalkyl, halo, hydroxy, and amino.

The term “-aralkyl” refers to an alkylene group substituted with an arylgroup. Suitable aralkyl groups include benzyl, picolyl, and the like,and may be optionally substituted. “Heteroarylalkyl” refers to analkylene group substituted with a heteroaryl group.

The term “alkylaryl-” refers to an aryl group substituted with an alkylgroup. “Lower alkylaryl-” refers to such groups where alkyl is loweralkyl.

The term “lower” referred to herein in connection with organic radicalsor compounds respectively defines such as with up to and including 10,in one aspect up to and including 6, and in another aspect one to fourcarbon atoms. Such groups may be straight chain, branched, or cyclic.

The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that arecyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 or 3 to 8carbon atoms. Suitable cyclic groups include norbornyl and cyclopropyl.Such groups may be substituted.

The term “heterocyclic”, “heterocyclic alkyl” or “heterocycloalkyl”refers to cyclic groups of 3 to 10 atoms, and in one aspect are 3 to 6atoms, containing at least one heteroatom, in a further aspect are 1 to3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, andnitrogen. Heterocyclic groups may be attached through a nitrogen orthrough a carbon atom in the ring. The heterocyclic alkyl groups includeunsaturated cyclic, fused cyclic and spirocyclic groups. Suitableheterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl,and pyridyl.

The terms “arylamino” (a), and “aralkylamino” (b), respectively, referto the group —NRR′ wherein respectively, (a) R is aryl and R′ ishydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R isaralkyl and R′ is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl.

The term “acyl” refers to —C(O)R where R is alkyl, heterocycloalkyl, oraryl.

The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl,aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.

The term “carboxyl” refers to —C(O)OH.

The term “oxo” refers to ═O in an alkyl or heterocycloalkyl group.

The term “amino” refers to —NRR′ where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, allexcept H are optionally substituted; and R and R′ can form a cyclic ringsystem.

The term “-carboxylamido” refers to —CONR₂ where each R is independentlyhydrogen or alkyl.

The term “-sulphonylamido” or “-sulfonylamido” refers to —S(═O)₂NR₂where each R is independently hydrogen or alkyl.

The term “halogen” or “halo” refers to —F, —Cl, —Br and —I.

The term “alkylaminoalkylcarboxy” refers to the groupalkyl-NR-alk-C(O)—O— where “alk” is an alkylene group, and R is an H orlower alkyl.

The term “sulphonyl” or “sulfonyl” refers to —SO₂R, where R is H, alkyl,aryl, aralkyl, or heterocycloalkyl.

The term “sulphonate” or “sulfonate” refers to —SO₂OR, where R is —H,alkyl, aryl, aralkyl, or heterocycloalkyl.

The term “alkenyl” refers to unsaturated groups which have 2 to 12 atomsand contain at least one carbon-carbon double bond and includesstraight-chain, branched-chain and cyclic groups. Alkenyl groups may beoptionally substituted. Suitable alkenyl groups include allyl.“1-alkenyl” refers to alkenyl groups where the double bond is betweenthe first and second carbon atom. If the 1-alkenyl group is attached toanother group, e.g., it is a W substituent attached to the cyclicphosphonate, it is attached at the first carbon.

The term “alkynyl” refers to unsaturated groups which have 2 to 12 atomsand contain at least one carbon-carbon triple bond and includesstraight-chain, branched-chain and cyclic groups. Alkynyl groups may beoptionally substituted. Suitable alkynyl groups include ethynyl.“1-alkynyl” refers to alkynyl groups where the triple bond is betweenthe first and second carbon atom. If the 1-alkynyl group is attached toanother group, e.g., it is a W substituent attached to the cyclicphosphonate, it is attached at the first carbon.

The term “alkylene” refers to a divalent straight chain, branched chainor cyclic saturated aliphatic group. In one aspect the alkylene groupcontains up to and including 10 atoms. In another aspect the alkylenechain contains up to and including 6 atoms. In a further aspect thealkylene groups contains up to and including 4 atoms. The alkylene groupcan be either straight, branched or cyclic.

The term “acyloxy” refers to the ester group —O—C(O)R, where R is H,alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

The term “aminoalkyl-” refers to the group NR₂-alk- wherein “alk” is analkylene group and R is selected from —H, alkyl, aryl, aralkyl, andheterocycloalkyl.

The term “alkylaminoalkyl-” refers to the group alkyl-NR-alk- whereineach “alk” is an independently selected alkylene, and R is H or loweralkyl. “Lower alkylaminoalkyl-” refers to groups where the alkyl and thealkylene group is lower alkyl and alkylene, respectively.

The term “arylaminoalkyl-” refers to the group aryl-NR-alk- wherein“alk” is an alkylene group and R is —H, alkyl, aryl, aralkyl, orheterocycloalkyl. In “lower arylaminoalkyl-”, the alkylene group islower alkylene.

The term “alkylaminoaryl-” refers to the group alkyl-NR-aryl- wherein“aryl” is a divalent group and R is —H, alkyl, aralkyl, orheterocycloalkyl. In “lower alkylaminoaryl-”, the alkyl group is loweralkyl.

The term “alkoxyaryl-” refers to an aryl group substituted with analkyloxy group. In “lower alkyloxyaryl-”, the alkyl group is loweralkyl.

The term “aryloxyalkyl-” refers to an alkyl group substituted with anaryloxy group.

The term “aralkyloxyalkyl-” refers to the group aryl-alk-O-alk- wherein“alk” is an alkylene group. “Lower aralkyloxyalkyl-” refers to suchgroups where the alkylene groups are lower alkylene.

The term “alkoxy-” or “alkyloxy-” refers to the group alkyl-O—.

The term “alkoxyalkyl-” or “alkyloxyalkyl-” refers to the groupalkyl-O-alk- wherein “alk” is an alkylene group. In “loweralkoxyalkyl-”, each alkyl and alkylene is lower alkyl and alkylene,respectively.

The terms “alkylthio-” and “alkylthio-” refer to the group alkyl-S—.

The term “alkylthioalkyl-” refers to the group alkyl-S-alk- wherein“alk” is an alkylene group. In “lower alkylthioalkyl-” each alkyl andalkylene is lower alkyl and alkylene, respectively.

The term “alkoxycarbonyloxy-” refers to alkyl-O—C(O)—O—.

The term “aryloxycarbonyloxy-” refers to aryl-O—C(O)—O—.

The term “alkylthiocarbonyloxy-” refers to alkyl-S—C(O)—O—.

The term “amido” refers to the NR₂ group next to an acyl or sulfonylgroup as in NR₂—C(O)—, RC(O)—NR¹—, NR₂—S(═O)₂— and RS(═O)₂—NR¹—, where Rand R¹ include —H, alkyl, aryl, aralkyl, and heterocycloalkyl.

The term “carboxamido” refers to NR₂—C(O)— and RC(O)—NR¹—, where R andR¹ include —H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term doesnot include urea, —NR—C(O)—NR—.

The terms “sulphonamido” or “sulfonamido” refer to NR₂—S(═O)₂— andRS(═O)₂—NR¹—, where R and R¹ include —H, alkyl, aryl, aralkyl, andheterocycloalkyl. The term does not include sulfonylurea,—NR—S(═O)₂—NR—.

The terms “carboxamidoalkylaryl” and “carboxamidoaryl” refer to anaryl-alk-NR¹—C(O), and ar-NR¹—C(O)-alk-, respectively where “ar” isaryl, “alk” is alkylene, R¹ and R include H, alkyl, aryl, aralkyl, andheterocycloalkyl.

The terms “sulfonamidoalkylaryl” and “sulfonamidoaryl” refer to anaryl-alk-NR¹—S(═O)₂—, and ar-NR¹—S(═O)₂—, respectively where “ar” isaryl, “alk” is alkylene, R¹ and R include —H, alkyl, aryl, aralkyl, andheterocycloalkyl.

The term “hydroxyalkyl” refers to an alkyl group substituted with one—OH.

The term “haloalkyl” refers to an alkyl group substituted with one halo.

The term “cyano” refers to —C≡N.

The term “nitro” refers to —NO₂.

The term “acylalkyl” refers to an alkyl-C(O)-alk-, where “alk” isalkylene.

The term “aminocarboxamidoalkyl-” refers to the group NR₂—C(O)—N(R)-alk-wherein R is an alkyl group or H and “alk” is an alkylene group. “Loweraminocarboxamidoalkyl-” refers to such groups wherein “alk” is loweralkylene.

The term “heteroarylalkyl” refers to an alkylene group substituted witha heteroaryl group.

The term “perhalo” refers to groups wherein every C—H bond has beenreplaced with a C-halo bond on an aliphatic or aryl group. Suitableperhaloalkyl groups include —CF₃ and —CFCl₂.

The term “carboxylic acid moiety” refers to a compound having acarboxylic acid group (—COOH), and salts thereof, a carboxylic acidester, or a carboxylic acid surrogate. Suitable carboxylic acidsurrogates include a tetrazole group, a hydroxamic acid group, athiazolidinedione group, an acylsulfonamide group, and a 6-azauracil.(see, e.g., The Practice of Medicinal Chemistry; Wemuth, C. G., Ed.;Academic Press: New York, 1996; p. 203).

The phrase “therapeutically effective amount” means an amount of acompound or a combination of compounds that ameliorates, attenuates oreliminates one or more of the symptoms of a particular disease orcondition or prevents, modifies, or delays the onset of one or more ofthe symptoms of a particular disease or condition.

The term “pharmaceutically acceptable salt” includes salts of compoundsof Formula I and its prodrugs derived from the combination of a compoundof this invention and an organic or inorganic acid or base. Suitableacids include acetic acid, adipic acid, benzenesulfonic acid,(+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid,citric acid, 1,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaricacid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid,hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonicacid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid,methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid,nitric acid, oleic acid,4,4′-methylenebis[3-hydroxy-2-naphthalenecarboxylic acid], phosphoricacid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid,sulfosalicylic acid, tannic acid, tartaric acid, terphthalic acid, andp-toluenesulfonic acid.

The term “patient” means an animal.

The term “animal” includes birds and mammals, in one embodiment amammal, including a dog, cat, cow, horse, goat, sheep, pig or human. Inone embodiment the animal is a human. In another embodiment the animalis a male. In another embodiment the animal is a female.

The term “hypercholesterolemia” refers to presence of an abnormallylarge amount of cholesterol in the cells and plasma of the circulatingblood.

The term “hyperlipidemia” or “lipemia” refers to the presence of anabnormally large amount of lipids in the circulating blood.

The term “atherosclerosis” refers to a condition characterized byirregularly distributed lipid deposits in the intima of large andmedium-sized arteries wherein such deposits provoke fibrosis andcalcification. Atherosclerosis raises the risk of angina, stroke, heartattack, or other cardiac or cardiovascular conditions.

The term “obesity” refers to the condition of being obese. Being obeseis defined as a BMI of 30.0 or greater; and extreme obesity is definedat a BMI of 40 or greater. “Overweight” is defined as a body mass indexof 25.0 to 29.9. (This is generally about 10 percent over an ideal bodyweight.)

The term “impaired glucose tolerance (IGT)” refers to a condition knownto precede the development of overt type 2 diabetes. It is characterizedby abnormal blood glucose excursions following a meal. The currentcriteria for the diagnosis of IGT are based on 2-h plasma glucose levelspost a 75 g oral glucose test (144-199 mg/dL). Although variable frompopulation to population studied, IGT progresses to full blown NIDDM ata rate of 1.5 to 7.3% per year, with a mean of 3-4% per year.Individuals with IGT are believed to have a 6 to 10-fold increased riskin developing NIDDM. IGT is an independent risk factor for thedevelopment of cardiovascular disease.

The term “insulin resistance” is defined clinically as the impairedability of a known quantity of exogenous or endogenous insulin toincrease whole body glucose uptake and utilization. As insulin regulatesa wide variety of metabolic processes in addition to glucose homeostasis(e.g., lipid and protein metabolism), the manifestations of insulinresistance are diverse and include one or more of the following: glucoseintolerance, hyperinsulinemia, a characteristic dyslipidemia (hightriglycerides; low high-density lipoprotein cholesterol, and small,dense low-density lipoprotein cholesterol), obesity, upper-body fatdistribution, fat accumulation in the liver (non-alcoholic fatty liverdisease), NASH (non-alcoholic steatohepatitis), increased hepaticglucose output, reduced hepatic glucose uptake and storage intoglycogen, hypertension, and increased prothrombotic and antifibrinolyticfactors. This cluster of cardiovascular-metabolic abnormalities iscommonly referred to as “The Insulin Resistance Syndrome” or “TheMetabolic Syndrome” and may lead to the development of type 2 diabetes,accelerated atherosclerosis, hypertension or polycystic ovariansyndrome.

The “Metabolic Syndrome” or “Metabolic Syndrome X” is characterized by agroup of metabolic risk factors in one person. They include:

-   -   Central obesity (excessive fat tissue in and around the abdomen)    -   Atherogenic dyslipidemia (blood fat disorders—mainly high        triglycerides and low HDL cholesterol—that foster plaque        buildups in artery walls)    -   Raised blood pressure (130/85 mmHg or higher)    -   Insulin resistance or glucose intolerance (the body can't        properly use insulin or blood sugar)    -   Prothrombotic state (e.g., high fibrinogen or plasminogen        activator inhibitor [−1] in the blood)    -   Proinflammatory state (e.g., elevated high-sensitivity        C-reactive protein in the blood)

According to the present invention, “Metabolic Syndrome” or “MetabolicSyndrome X” is identified by the presence of three or more of thesecomponents:

-   -   Central obesity as measured by waist circumference:

Men: Greater than 40 inches

Women: Greater than 35 inches

-   -   Fasting blood triglycerides greater than or equal to 150 mg/dL    -   Blood HDL cholesterol:    -   Men: Less than 40 mg/dL    -   Women: Less than 50 mg/dL    -   Blood pressure greater than or equal to 130/85 mmHg    -   Fasting glucose greater than or equal to 110 mg/dL

The term “metabolic disease” includes diseases and conditions such asobesity, diabetes and lipid disorders such as hypercholesterolemia,hyperlipidemia, hypertriglyceridemia as well as disorders that areassociated with abnormal levels of lipoproteins, lipids, carbohydratesand insulin such as metabolic syndrome X, diabetes, impaired glucosetolerance, atherosclerosis, coronary heart disease, cardiovasculardisease.

As used herein, the term “significant” or “statistically significant”means a result (i.e. experimental assay result) where the p-value is≤0.05 (i.e. the chance of a type I error is less than 5%) as determinedby an art-accepted measure of statistical significance appropriate tothe experimental design.

The present invention provides compounds that are useful for treating orpreventing conditions and disorders associated with DGAT in mammals,particularly humans. One aspect of the invention is directed towards thecompounds represented by Formula (I), pharmaceutically acceptable saltsor stereoisomers thereof,Q-G¹-G²-G³-G⁴-Z  Formula (I)

wherein

Q is Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷, Q⁸, or Q⁹, as defined herein and foreach of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷, Q⁸, or Q⁹, common substituents foundin the structures are defined as follows:

R¹ is selected from the group consisting of H, (C₁-C₈)alkyl,halo(C₁-C₄)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, C(O)R^(a), OR^(a) andNR^(a)R^(b); optionally, when X is C(R⁴), R^(a) or R^(b) may be combinedwith R⁴ or R⁴ may be combined with R¹ to form a 5-, 6- or 7-memberedfused ring;

R^(a) and R^(b) are independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, fluoro(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, aryl, heteroaryl and aryl(C₁-C₄)alkyl;

R² and R³ are independently selected from the group consisting of H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, C(O)R^(a), CO₂R^(a),C(O)NR^(a)R^(b), (C₁-C₄)alkylene-OR^(a) and (C₁-C₄)perfluoroalkyl; or R²and R³ may be combined to form a 3-, 4-, 5- or 6-membered spiro ring;optionally, having from 0 to 3 heteroatoms selected from the groupconsisting of N, O and S;

each R⁴ is independently selected from the group consisting of H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, fluoro(C₁-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, C(O)R^(a), CO₂R^(a) and C(O)NR^(a)R^(b);

R⁶ is an optionally substituted aryl or optionally substitutedheteroaryl group, wherein the optional substituents are one or moregroups selected from H, (C₁-C₄)alkyl, halo, halo(C₁-C₄)alkyl, cyano,(C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, —C(O)_(x)R^(a), —OR^(a),—S(O)_(x)R^(a), —NR^(a)R^(b), —C(O)NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)CO NR^(a)R^(b), —S(O)₂NR^(a)R^(b) or —NR^(a)S(O)₂NR^(a)R^(b)where x is an integer of 1 or 2;

T is N, CH or CMe;

R⁸ is independently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,aryl, heteroaryl, (C₃-C₈)cycloalkyl, cyano, (C₁-C₆)haloalkyl,(C₁-C₆)haloalkoxy, —OR^(a), —O—C(O)(R^(a)), —S(R^(a)), —S(O)(R^(b)),—S(O)₂(R^(b)), —C(O)(R^(a)), —C(O)(OR^(a)), —N(R^(a))₂,—N(R^(a))—C(O)(R^(a)), —C(O)N(R^(a))₂, —S(O)₂N(R^(a))₂,—(CR^(a)R^(b))_(t)OR^(a), —(CR^(a)R^(b))_(t)—O—C(O)(R^(a)),—(CR^(a)R^(b))_(t)S(R^(a)), —(CR^(a)R^(b))_(t)S(O)(R^(b)),—(CR^(a)R^(b))_(t)S(O)₂(R^(b)), —(CR^(a)R^(a))_(t)C(O)(R^(a)),—(CR^(a)R^(b))_(t)C(O)(OR^(a)), —(CR^(a)R^(b))_(r)N(R^(a) R^(b))—(CR^(a)R^(b))_(t)N(R^(a))—C(O)(R^(a)), —(CR^(a)R^(b))_(t)C(O)N(R^(a))₂,—(CR^(a)R^(a))_(t)S(O)₂N(R^(a))₂ or —(CR^(a)R^(b))_(t)R^(a) and whereint is an integer of 1, 2, 3, or 4;

Q¹ is

wherein J is selected from —NR^(a)R^(b) or —OR^(a);

X is selected from the group consisting of C(R⁴) and N; optionally, whenX is C(R⁴), R^(a) or R^(b) may be combined with R⁴ or R⁴ may be combinedwith R¹ to form a 5-, 6- or 7-membered fused ring;

E is selected from the group consisting of O and S;

Q² is

R⁵ is H or (C₁-C₄)alkyl;

X is N or C(R⁴) and when X is C(R⁴), R⁴ may be combined with R¹ to forma 5-, 6- or 7-membered fused ring;

R² and R³ are as defined above or may be combined with R⁵ to form a 3-,4-, 5- or 6-membered spiro ring; optionally, having from 0 to 3heteroatoms selected from the group consisting of N, O and S;

Q³ is

Q⁴ is

Q⁵ is

Q⁶ is

R⁷(V)_(n)C(O)(NH)_(m)—;

R⁷ is (C₁-C₈)alkyl, aryl, heteroaryl or (C₃-C₈)cycloalkyl; wherein eachof the aryl, heteroaryl and cycloalkyl is independently substituted with1, 2, 3, 4, or 5 substituents independently selected from the groupconsisting of (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, —CN,halogen, ethylenedioxy, methylenedioxy, haloalkyl, —OR^(a),—O—C(O)(R^(a)), —S(R^(a)), —S(O)(R^(b)), —S(O)₂(R^(b)), —C(O)(R^(a)),—C(O)(OR^(a)), —N(R^(a))₂, —N(R^(a))—C(O)(R^(a)), —C(O)N(R^(a))₂,—S(O)₂N(R^(a))₂, —(CR^(a)R^(b))_(t)OR^(a),—(CR^(a)R^(b))_(t)—O—C(O)(R^(a)), —(CR^(a)R^(b))_(t)S(R^(a)),—(CR^(a)R^(b))_(t)S(O)(R^(b)), —(CR^(a)R^(b))_(t)S(O)₂(R^(b)),—(CR^(a)R^(a))_(t)C(O)(R^(a)), —(CR^(a)R^(b))_(t)C(O)(OR^(a)),—(CR^(a)R^(b))_(r)N(R^(a) R^(b)) —(CR^(a)R^(b))_(t)N(R^(a))—C(O)(R^(a)),—(CR^(a)R^(b))_(t)C(O)N(R^(a))₂, —(CR^(a)R^(a))_(t)S(O)₂N(R^(a))₂ and—(CR^(a)R^(b))_(t)R^(a),

V is —NH—, —O—, —(CR^(a)R^(b))_(t)—;

where t is an integer of 1, 2, 3, or 4;

m is 0 or 1;

n is 0 or 1;

Q⁷ is

wherein D is O, NR^(c), or S; and

A is a fused ring selected from an aromatic 6-membered ring containing 0or 2 N atoms;

the number of R⁸ substituents on A ring may be 0, 1 or 2 and when two ofsaid R⁸ substituents are: a) found on A ring; b) (C₁-C₆)alkyl and c)attached to adjacent carbon atoms of the Ring A, they may be joinedtogether to form a 5 to 7-membered carbocyclic ring; and

R^(c) is H or (C₁-C₆)alkyl, hydroxyl(C₂-C₆)alkyl;

Q⁸ is

L is N or C(R⁸); and

the number of R⁸ substituents on A ring may be 0, 1, 2 or 3 and when twoof said R⁸ substituents are: a) found on A ring; b) (C₁-C₆)alkyl and c)attached to adjacent carbon atoms of the Ring A, they may be joinedtogether to form a 5- to 7-membered carbocyclic ring containing 0, 1, 2or 3 heteroatoms selected from O, N, S; or

Q⁹ is a [5,5], [5,6], [6,5] and [6,6] bicylic heterocycle containing 1to 4 N atoms where G¹ is connected through one of the ring N atoms;

G¹ and G³ are independently selected from the group consisting ofcyclo(C₃-C₈)alkylene, heterocyclo(C₃-C₈)alkylene, arylene andheteroarylene, optionally substituted with one or two groupsindependently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkoxy, cyano, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy,(C₁-C₄)perfluoroalkyl; —N(R^(a)R^(b)), —N(R^(a))—C(O)(R^(a)),—C(O)N(R^(a))₂, —S(O)₂N(R^(a))₂ —S(O)₂(R^(b))and —C(O)(R^(a)).

G² is selected from the group consisting of a bond, (C₁-C₄)alkylene,(C₂-C₄)alkenylene, O, N(R^(a))C(O), S and S(O)₂;

G⁴ is -X—Y—

wherein X is selected from null, O, NH, CO, CHOH, S or S(O)₂; and Y isselected from (C₁-C₄)alkylene, (C₃-C₈)-cycloalkylene or(C₃-C₈)-heterocycloalkylene, —CH(R⁹)C(R¹⁰R¹¹)— or —N(R⁹)C(R¹⁰R¹¹)—

wherein

R¹⁰ and R¹¹ are both hydrogen, and R⁹ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₂-C₆)alkenyl, phenoxy-(C₂-C₆)alkyl,1-methyl-1H-indol-3-yl, bis[(C₁-C₆)alkyl]amino-(C₂-C₆)alkyl,1-piperidinyl-(C₂-C₆)alkyl, 1-pyrrolidinyl-(C₂-C₆)alkyl, or1-morpholinyl-(C₂-C₆) alkyl;

or

R¹⁰ and R¹¹ are both hydrogen and R⁹ is R¹²(CH₂)_(m), where m is 0 to 3,and R¹² is phenyl optionally substituted with one or more halogen,hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl or cyano;

or

R¹⁰ and R¹¹ are both hydrogen and R⁹ is R¹²(CH₂)_(m), where m is 0 to 3,and R¹² is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, each of which isoptionally substituted with halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,trifluoromethyl or cyano; or

R⁹ is hydrogen, and R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached, form a three to five-membered ring, with 0 to 2heteroatoms independently selected from O, S or N; or R¹⁰ is hydrogen,and R⁹ and R¹¹ together with the two carbon atoms to which they areattached, form a three- to six-membered ring with 0 to 2 heteroatomsindependently selected from O, S or N;

Z is Z¹ or Z² as defined herein;

Z¹ is

X¹ and X² are independently selected from null, (C(R^(a)R^(b)))_(n), O,NR^(a), S or CO and n is 0 or 1; W is selected from H, (C₁-C₆)alkyl,aryl, heteroaryl or (C₃-C₈)cycloalkyl; wherein each of the alkyl, aryl,heteroaryl and cycloalkyl is independently substituted with 1, 2, 3, 4,or 5 substituents independently selected from the group consisting of(C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, —CN, halogen,ethylenedioxy, methylenedioxy, haloalkyl, —OR^(a), —O—C(O)(R^(a)),—S(R^(a)), —S(O)(R^(b)), —S(O)₂(R^(b)), —C(O)(R^(a)), —C(O)(OR^(a)),—N(R^(a))₂, —N(R^(a))—C(O)(R^(a)), —C(O)N(R^(a))₂, —S(O)₂N(R^(a))₂,—(CR^(a)R^(b))_(t)OR^(a), —(CR^(a)R^(b))_(t)—O—C(O)(R^(a)),—(CR^(a)R^(b))_(t)S(R^(a)), —(CR^(a)R^(b))_(t)S(O) (R^(b)),—(CR^(a)R^(b))_(t)S(O)₂(R^(b)), —(CR^(a)R^(a))_(t)C(O)(R^(a)),—(CR^(a)R^(b))_(t)C(O)(OR^(a)),—(CR^(a)R^(b))_(t)N(R^(a)R^(b))—(CR^(a)R^(b))_(t)N(R^(a))—C(O)(R^(a)),—(CR^(a)R^(b))_(t)C(O)N(R^(a))₂, —(CR^(a)R^(a))_(t)S(O)₂N(R^(a))₂ and—(CR^(a)R^(b))_(t)R^(a), —(CR^(a)R^(b))_(t)P(O)(OH)₂, and—(CR^(a)R^(b))_(t)P(O)(OH)(R^(a)), wherein t is an integer of 1, 2, 3,or 4;

X¹ and X² may be combined to form a 5-, 6- or 7-membered ring havingfrom 0 to 3 heteroatoms selected from the group consisting of NR^(a), Oand S; or X¹ or X² may be combined with W to form a 5-, 6- or 7-memberedfused ring having from 0 to 3 heteroatoms selected from the groupconsisting of NR^(a), O and S;

Z² is Z¹, H, —OH, CO₂R^(a) or —C(O)N(R^(a))₂;

with a proviso that when X² is O and Q is Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷ orQ⁹, then X¹ is not (C(R^(a)R^(b)))_(n) and when Q is Q⁸ then Z is Z² andZ² is Z¹, H, —OH, CO₂R^(a) or —C(O)N(R^(a))₂.

Another aspect of the invention provides for pharmaceutically acceptablesalts of the compounds of Formula (I), in addition to those discussed inthe definitions section of this application. Such salts include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, and undecanoate. Base salts includealkali metal salts such as potassium and sodium salts, alkaline earthmetal salts such as calcium and magnesium salts, and ammonium salts withorganic bases such as dicyclohexylamine salts and N-methyl-D-glucamine.Additionally, basic nitrogen containing groups may be quaternized withsuch agents as lower alkyl halides such as methyl, ethyl, propyl, andbutyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl,diethyl, and dibutyl sulfate and diamyl sulfates; long chain halidessuch as decyl, lauryl, myristyl and strearyl chlorides, bromides, andiodides; aralkyl halides like benzyl and phenethyl bromides and others.

Another aspect of the invention provides pharmaceutical compositionsformed by combining the compounds of this invention withpharmaceutically acceptable carriers, vehicles or diluents. Thesepharmaceutically acceptable compositions can, then, be administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders and/or excipients.

Thus, one aspect of the invention provides pharmaceutical compositionfor oral administration. For example, tablets containing variousexcipients such as sodium citrate, calcium carbonate and/or calciumphosphate, may be employed along with various disintegrants such asstarch, alginic acid and/or certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin and/oracacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions comprising the aforementioned excipients,disintegrants and/or lubricating agents may also be employed as fillersin soft and hard filled gelatin capsules. Additionally, materials suchas lactose or milk sugar and high molecular weight polyethylene glycolscan also be utilized in the preparation of soft or hard capsulesdisclosed herein. When aqueous suspensions or elixirs are desired fororal administration, the active pharmaceutical agent therein may becombined with various sweetening or flavoring agents, coloring matter ordyes and, if desired, emulsifying or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin and/orcombinations thereof. Tablets and capsules disclosed herein can also beformulated with enteric coatings known to those skilled in the art.

For parenteral administration, solutions comprising compounds disclosedherein can be formulated in oils (such as sesame or peanut oil), aqueouspropylene glycol, or in sterile aqueous solutions. Aqueous solutionsshould be suitably buffered, if necessary, and the liquid diluent firstrendered isotonic with sufficient saline or glucose. Compoundsformulated as discussed herein are suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media employed are all readily availableby standard techniques known to those skilled in the art.

For intranasal administration or administration by inhalation, thecompounds or compositions of the invention are conveniently delivered inthe form of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of a compound of thisinvention. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound or compounds of the invention and a suitable powderbase such as lactose or starch.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. Methods of preparingpharmaceutical compositions are known to those skilled in the art (seeRemington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 19th Edition (1995)).

In another aspect of the invention, methods of inhibiting or reducingthe activity of DGAT-1 in enterocytes are provided that comprisecontacting an enterocyte with a composition comprising a compound ofFormula (I), or a pharmaceutically acceptable salt of a compound ofFormula (I). In this aspect of the invention, the enterocyte iscontacted with an amount of the composition sufficient to inhibit DGAT-1activity within the cell. This method can be conducted in vitro or invivo.

The terms “treating”, “treated”, or “treatment” as employed hereinincludes palliating, slowing progression and/or reducing symptomsassociated with a disease, such as obesity, insulin resistance syndrome,Type 2 diabetes, or adiposity. The phrase “therapeutically effectiveamount” means an amount of a compound of the present invention that (i)treats the particular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) delays the onset of one ormore symptoms of the particular disease, condition, or disorderdescribed herein.

In another aspect of the invention, methods of treating a disease orcondition amenable to treatment via DGAT-1 inhibition are provided.These methods comprise administering to a mammal a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt of the compound, either alone or in combination with ananti-diabetic agent as described above. Conditions that can be treatedin this aspect of the invention include Type 2 diabetes, insulinresistance syndrome, obesity, impaired glucose tolerance, hyperglycemia,high postprandial triglycerides (very common in diabetes) or diet- orobesity-related hypertriglyceridemia, cardiovascular risk associatedwith excessive triglycerides, and insulin resistance and glucoseintolerance (e.g., improved insulin sensitivity due to reduceddeposition of liver and skeletal muscle fat) seen in overweightpatients, those with diabetes or other glucose metabolic disorders suchas Syndrome X, polycystic ovary disease or other disorders such asdiabetic complications that arise from obesity.

The present invention also relates to therapeutic methods for treatingthe above described conditions in a mammal, including a human, wherein acompound of Formula (I) is administered as part of an appropriate dosageregimen designed to obtain the benefits of the therapy. The appropriatedosage regimen, the amount of each dose administered and the intervalsbetween doses of the compound will depend upon the compound of Formula(I) of this invention being used, the type of pharmaceuticalcompositions being used, the characteristics of the subject beingtreated and the severity of the conditions.

In general, an effective dosage for the compounds of the presentinvention is in the range of 0.01 mg/kg/day to 1000 mg/kg/day,preferably 0.01 mg/kg/day to 600 mg/kg/day of active compound (i.e., acompound of Formula (I)) in single or divided doses (for example, threedoses of 200 mg/kg over the course of a day). Some variation in dosagewill necessarily occur, however, depending on the condition of thesubject being treated. The individual responsible for dosing will, inany event, determine the appropriate dose for the individual subject.Practitioners will appreciate that “kg” refers to the weight of thesubject measured in kilograms.

The compounds or compositions of this invention may be administered insingle (e.g., once daily) or multiple doses or via constant infusion.The compounds of this invention may also be administered alone or incombination with pharmaceutically acceptable carriers, vehicles ordiluents, in either single or multiple doses. The compounds orcompositions of the present invention may be administered to a subjectin need of treatment by a variety of conventional routes ofadministration, including orally and parenterally, (e.g., intravenouslyor subcutaneously). Further, the pharmaceutical compositions of thisinvention may be administered intranasally, as a suppository, or using a“flash” formulation, i.e., allowing the medication to dissolve in themouth without the need to use water. The compounds are preferablydelivered via a route that accesses the alimentary tract, e.g., orallyor nasally.

Combination therapies utilizing compounds of Formula (I) are provided byyet another aspect of the invention. Thus, compounds of Formula (I) canbe administered in combination (concomitantly or sequentially and as asingle combined composition or as separate compositions that areseparately administered), with anti-diabetic and/or anti-obesity agentsknown to those skilled in the art. Non-limiting examples of anti-obesityagents include: 1) central nervous system agents that affectneurotransmitters or neural ion channels, including antidepressants(bupropion), selective serotonin 2c receptor agonists, antiseizureagents (topiramate, zonisamide), some dopamine antagonists, andcannabinoid-1 receptor antagonists (rimonabant); 2)leptin/insulin/central nervous system pathway agents, including leptinanalogues, leptin transport and/or leptin receptor promoters, ciliaryneurotrophic factor (Axokine), neuropeptide Y and agouti-related peptideantagonists, proopiomelanocortin and cocaine and amphetamine regulatedtranscript promoters, alpha-melanocyte-stimulating hormone analogues,melanocortin-4 receptor agonists, and agents that affect insulinmetabolism/activity, which include protein-tyrosine phosphatase-1Binhibitors, peroxisome proliferator activated receptor-gamma receptorantagonists, short-acting bromocriptine (ergoset), somatostatin agonists(octreotide), and adiponectin; 3) gastrointestinal-neural pathwayagents, including those that increase cholecystokinin activity, increaseglucagon-like peptide-1 activity (extendin 4, liraglutide, dipeptidylpeptidase IV inhibitors), and increase protein YY3-36 activity and thosethat decrease ghrelin activity, as well as amylin analogues(pramlintide); 4) agents that may increase resting metabolic rate(“selective” beta-3 stimulators/agonist, uncoupling protein homologues,and thyroid receptor agonists); and 5) other more diverse agents,including melanin concentrating hormone antagonists, phytostanolanalogues, functional oils, P57, amylase inhibitors, growth hormonefragments, synthetic analogues of dehydroepiandrosterone sulfate,antagonists of adipocyte 11B-hydroxysteroid dehydrogenase type 1activity, corticotropin-releasing hormone agonists, inhibitors of fattyacid synthesis, carboxypeptidase inhibitors, indanones/indanols,aminosterols, and other gastrointestinal lipase inhibitors (ATL962).Anti-diabetic agents that can be used in the aforementioned combinationtherapies include, and are not limited to: insulin; sulfonylureacompounds, such as glyburide, tolbutamide, acetohexamide, tolazamide,chlorpropamide, glipizide, glimepiride or gliclazide; meglitinides, suchas repaglinide or nateglinide; biguanides, such as metformin, phenforminor buformin; thiazolidinediones, such as rosigliazone, pioglitozone ortroglitazone, alpha-glucosidase inhibitors, such as miglitol orasarabose; peptides or peptide analogs, such as glucagon-like peptide 1,gastric inhibitory peptide, exenatide, exendin-4, liraglutide ortaspoglatide; DPP-IV inhibitors, such as vildagliptin or sitaliptin;amylin analogs, such as pramlintide; PPARα/γ ligands, such asaleglitazar, muraglitazar or tesaglitazar; SGLT (sodium-dependentglucose transporter 1) or FBPase (fructose 1,6-bisphosphatase)inhibitors, such as those disclosed in U.S. Pat. Nos. 6,967,193;6,965,033; 6,919,322; 6,489,476; 6,399,782; or 6,110,903 each of whichis hereby incorporated by reference in its entirety.

EXAMPLES

Numerous compounds of the invention have been synthesized and shown totarget enterocytes and exhibit inhibition of DGAT-1. Various data areshown by way of example below. The physical characteristics of somemolecules of the invention are included in Table 1 below.

TABLE 1 Elemental Analysis and Mass Spec Data of Certain Compounds ofthe Present Invention Elemental Analysis CHN (calcd) Compound CHN(Found) Mass Spec Number Structure Formula MH+  1

C: 60.40, H: 6.91, N: 12.81 C: 60.81, H: 7.29, N: 12.42 C₂₂H₂₉N₄O₃P +0.5 H₂O 492  2

C: 64.99, H: 6.08, N: 5.83 C: 64.75, H: 6.03, N: 5.40 C₂₆H₂₇N₂O₄P + 1.0H₂O 463  3

C: 53.82, H: 6.59, N: 11.52 C: 53.55, H: 6.24, N: 11.64 C₂₀H₂₅N₄O₅P +1.0 H₂O + 0.6 i-PrOH 433  4

C: 56.24, H: 6.52, N: 12.49 C: 55.76, H: 6.57, N: 12.13 C₂₁H₂₇N₄O₄P +1.0 H₂O 431  5

C: 55.31, H: 5.25, N: 11.22 C: 55.11, H: 4.87, N: 11.18 C₂₃H₂₅F₂N₄O₄P +0.5 H₂O 491  6

C: 50.18, H: 4.90, N: 12.72 C: 50.13, H: 4.66, N: 12.80 C₁₈H₂₀ClN₄O₃P +0.6 H₂O + 0.2 CF₃CO₂H 407  7

C: 56.93, H: 6.61, N: 6.64 C: 57.09, H: 6.68, N: 6.81 C₂₄H₂₇N₂O₅P + 2.5H₂O + 0.4 NH₃ 455  8

C: 57.73, H: 6.90, N: 11.22 C: 57.78, H: 7.28, N: 10.79 C₂₄H₃₃N₄O₅P +0.6 H₂O 489  9

C: 51.36, H: 6.86, N: 10.89 C: 50.96, H: 6.49, N: 10.60 C₂₂H₂₉N₄O₅P +3.0 H₂O 461 10

C: 53.62, H: 7.13, N: 10.01 C: 53.21, H: 6.54, N: 9.84 C₂₅H₃₃N₄O₅P + 3.3H₂O 501 11

C: 61.82, H: 6.34, N: 10.68 C: 61.35, H: 6.20, N: 10.65 C₂₇H₃₁N₄O₄P +1.0 H₂O 507 12

C: 60.64, H: 6.36, N: 10.10 C: 60.98, H: 6.39, N: 9.62 C₂₈H₃₃N₄O₅P + 1.0H₂O 537 13

C: 56.26, H: 6.82, N: 11.93 C: 56.19, H: 6.69, N: 11.76 C₂₂H₂₉N₄O₄P +1.4 H₂O 445 14

C: 62.27, H: 6.03, N: 11.17 C: 61.88, H: 5.66, N: 11.02 C₂₆H₂₉N₄O₄P +0.5 H₂O 493 15

C: 55.65, H: 6.67, N: 10.74 C: 55.98, H: 7.07, N: 11.06 C₂₉H₃₅N₄O₃P +1.6 H₂O + 0.8 NH₄Br 519 16

C: 62.39, H: 7.45, N: 11.19 C: 62.61, H: 7.39, N: 11.40 C₂₆H₃₅N₄O₃P +1.0 H₂O 483 17

C: 58.23, H: 5.93, N: 9.70 C: 58.02, H: 5.61, N: 9.47 C₂₈H₃₁N₄O₆P + 1.5H₂O 551 18

C: 45.09, H: 4.83, N: 7.25 C: 44.95, H: 5.17, N: 6.98 C₂₈H₂₉N₄O₆PNa₂ +4.0 H₂O + 1.0 Na₂CO₃ 551 19

C: 57.00, H: 5.54, 11.08 C: 56.85, H: 5.57, N: 10.92 C₂₄H₂₇N₄O₄SP + 0.4H₂O 499 20

C: 57.00, H: 5.54, N: 11.08 C: 57.09, H: 5.39, N: 11.13 C₂₄H₂₇N₄O₄SP +0.4 H₂O 499 21

C: 64.92, H: 6.46, N: 11.22 C: 64.78, H: 6.49, N: 11.03 C₂₇H₃₁N₄O₃P +0.5 H₂O 491 22

C: 61.18, H: 7.14, N: 12.41 C: 61.33, H: 7.27, N: 12.26 C₂₃H₃₁N₄O₃P +0.5 H₂O 444 23

C: 62.19, H: 6.96, N: 12.09 C: 62.17, H: 6.87, N: 11.91 C₂₄H₃₁N₄O₃P +0.5 H₂O 455 24

425 25

C: 58.35, H: 6.07, N: 10.89 C: 59.34, H: 6.06, N: 10.86 C₂₅H₂₉N₄O₃PS + 1H₂O 497 26

C: 59.82, H: 5.94, N: 11.16 C: 60.04, H: 6.09, N: 10.94 C₂₅H₂₉N₄O₃PS +0.3 H₂O 497 27

C: 54.05, H: 5.66, N: 12.01 C: 54.36, H: 5.75, N: 11.54 C₂₁H₂₄ClN₄O₃P +1.1 H₂O 447 28

C: 56.13, H: 5.38, N: 10.91 C: 56.39, H: 5.38, N: 10.30 C₂₄H₂₄ClN₄O₃P +1.7 H₂O 483 29

C: 49.88, H: 6.05, N: 12.93 C: 49.67, H: 5.23, N: 12.82 C₁₈H₂₁N₄O₄P +2.5 H₂O 389 30

C: 57.67, H: 5.96, N: 12.93 C: 57.83, H: 5.80, N: 10.48 C₂₆H₃₀N₅O₅P +1.0 H₂O 524 31

C: 59.65, H: 5.78, N: 13.38 C: 59.68, H: 5.81, N: 10.84 C₂₆H₃₀N₅O₅P 52432

C: 61.92, H: 7.61, N: 11.55 C: 62.11, H: 8.15, N: 11.19 C₂₅H₃₅N₄O₃P +0.8 H₂O 471 33

C: 59.84, H: 7.49, N: 11.63 C: 59.64, H: 7.88, N: 11.31 C₂₄H₃₃N₄O₃P +1.4 H₂O 457 34

C: 60.22, H: 5.90, N: 10.40 C: 60.55, H: 6.30, N: 10.08 C₂₇H₃₀ClN₄O₃P +0.75 H₂O 525 35

C: 54.30, H: 5.87, N: 17.59 C: 54.59, H: 5.71, N: 17.17 C₁₈H₂₂N₅O₃P +0.6 H₂O 388 36

C: 51.03, H: 4.28, N: 11.44 C: 51.33, H: 4.40, N: 11.67 C₂₄H₂₅ClN₅O₃P +1.0 CF₃CO₂H 498 37

C: 48.16, H: 4.88, N: 12.42 C: 48.37, H: 4.96, N: 12.77 C₂₀H₂₆N₅O₃P +1.3 CF₃CO₂H 416 38

C: 52.23, H: 4.50, N: 11.45 C: 52.16, H: 4.40, N: 11.57 C₂₄H₂₆N₅O₃P +1.3 CF₃CO₂H 464 39

40

C: 58.06, H: 5.68, N: 15.05 C: 57.83, H: 5.68, N: 14.97 C₁₈H₂₁N₄O₃P 37341

415 42

417 43

423 44

590 45

534 46

384 47

294 48

309 49

328 50

313 51

491 52

390 53

449

Preparation of Compounds

The synthesis of compounds of Formula (I), wherein the groups Q, Q¹, Q²,Q³, Q⁴, Q⁵, Q⁶, Q⁷, Q⁸, Q⁹, G¹, G², G³, G⁴, Z, Z¹, Z², X, X¹, X², T, E,J, A, D, T, R^(a), R^(b), R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹² and integers t, m, or n have the meanings as set forth in theDetailed Description section unless otherwise noted, is exemplified inSchemes 1-8.

Compounds of the present invention can be prepared beginning withcommercially available starting materials and using general synthetictechniques known to those of skill in the art. Outlined below arereaction schemes suitable for preparing such compounds.

As illustrated in Scheme 1, compounds of formula 5 can be synthesizedstarting from commercially available compounds such as of formula 1.These carbonyl compounds upon Wittig type condensation withmethylenediphosphonate ester in presence of a base result in thehomologoted unsaturated phosphonate adducts (Xu et al, J. Org. Chem.,1996, 61, 7697-7701). The resulting olefins undergo facile hydrogenationto give trans-1,4- or 1,3-substituted (depending on n variable of thestarting materials of formula 1) compounds of formula 2. The conditionsof such hydrogenations may be similar to the earlier reported protocolsas in WO04047755. Preparation of compounds of formula 3 from 2 may beattained by selective preparation of monophosphonochloridate followed byreaction with aryl or heteroaryl or alkyl or cycloalkyl magnesiumhalides as previously reported (Morise et al, J. Chem. Soc. PerkinTrans. I, 1996, 2179-2185). Alternatively, H-phosphinates formed fromcompounds of formula 2 may be coupled to aryl or heteroaryl halide ortriflate under palladium catalyzed reaction conditions to introduce-X2-W group as in formula 3 (Bennett et al, J. Chem. Soc. Perkin Trans.I, 1995, 1145-1151). Synthesis of compounds of formula 4 from 3 can beattained as described earlier in WO04047755.

Deprotection of phosphorus ester of 4 can be achieved by a variety ofmethods depending on the choice of R′ group. Alkyl esters undergodeprotection under bromotrimethyl silane (TMSBr) hydrolysis conditions.Hexamethyl disilazane is used as an additive with TMSBr where thesubstrate is acid-sensitive. Acid mediated deprotection conditions areused for t-butyl esters. In case of phenyl substituted esters,deprotection may be achieved by base hydrolysis. Whereas, benzyl orallyl esters undergo deprotection in neutral conditions such ashydrogenation in the presence of a catalyst and reaction by palladiumcatalysis, respectively. These deprotection conditions exemplified forconversion of 4 to 5 may be utilized across all the synthetic sequencesthat are described herein (Schemes 1-8).

Alternatively, Z group substitution may be introduced at a later stageof the synthesis as shown in scheme 3. Such a synthetic strategy may beapplied to prepare compounds of formula 11 from 10 where Q issubstituted with Q¹, Q², Q³, Q⁴, Q⁵, Q⁸ or Q⁹. Compounds of formula 10can be attained following earlier described procedures in WO04047755,WO08067257, WO08134690, WO08134693, WO06064189, WO06134317, WO07071966,WO07138304, WO07138311, WO07141502, WO07141517, WO07141538, WO07141545,WO07144571, and WO08129319. Introduction of Z group substitution isaccomplished by coupling of compounds of formula 7 with 10. Suchcoupling reactions where X¹ of 10 is O or S and leaving group (LG) of 7is Cl or a substituted or non-substituted phenyl group can be achievedby magnesium alkoxides mediated reactions (WO07022073). Compounds offormula 7 may be synthesized by a nucleophilic displacement reaction of8. In addition, compounds of Formula 7 can be prepared by applying othermethods known in the art. For example, Pd-catalyzed reactions of aryl,heteroaryl or enol triflate (Kalek et al, Org. Lett., 2008, 10,4637-4640, Bonnaventure et al, J. Org. Chem. 2008, 73, 6330-6340) orbase mediated reactions of benzylic type of halides with phosphinate 9(Hubbard et al, Bioorg. Med. Chem. Lett., 2008, 18, 679-681. Boyd et al,Tetrahedron Lett., 1996, 37, 5425-5426; Ando et al, J Org. Chem., 1999,64, 8406-8408), or by a well-known Arbuzov type of reactions with 6(Perumal et al, J Org Chem., 2006, 71, 4778-4785).

Compounds that have heterocyclic substitution as in 15 may be obtainedfrom 13 via coupling of precursors of formula 12. Such sequence to 15may be a linear synthesis as in scheme 1 or convergent sequence as inscheme 3. Synthesis of compounds of formula 12 can be achieved fromcommercially available halomethylene phosphonate diesters via thetransformations that were described earlier in scheme 1, in theconversion of compounds of formula 2 to 3. Base mediated coupling of 12and 13 to 14 and conversion to 15 may be achieved as described inWO04047755.

Compounds of formula 17 (Scheme 4) can be synthesized from 16 where X′″is —OH or —NH₂ as described in WO09016462. Compounds of 16 where X′″ is—OH may be attained starting from a commercially available hydroxylsubstituted 1 following the chemistry described in scheme 1. Compoundswhere X′″ in 16 is —NH₂ are obtained by direct nitration and reductionsequence (WO07141502) from 2, or via 16 where X′″ is substituted with—OH, by Pd mediated amination of corresponding triflate (WO07141517).

The methods described for amine precursor 16 may also be applied in thepreparation of compounds of formula 19 with diverse G3 substitution.Such amines of 16 or 19 can be utilized in the synthesis of compounds offormulae of 20 to 22. Synthetic procedures described in WO05044250,WO06064189, WO06134317, WO07071966, WO07138304, WO07138311, WO07141502,WO07141517, WO07141538, WO07141545, WO07144571, WO08129319 may beutilized for the preparation of compounds of formulae of 20 to 22.

Compounds of formula 25 can be attained from 16 where X′″ is —NH₂, viadisplacement reaction of a commercially available substitutedpyrimidine, pyridine or a phenyl substituted precursor (23). Reductionof the resulting displacement product followed by cyclization with adesired R⁸ substituted carboxylic acid or aldehyde result in thecompounds of formula 25. Alternatively, compounds of 25 can be preparedvia a copper mediated N-arylation reaction of 26 and an appropriatelyfunctionalized heterocycle as 27 (Jacobsen et al, J. Org. Chem. 2006,71, 9183-9190).

Compounds of formulae 31 and 32 can be made from 29 where X″ is a groupselected from Br, I or triflate, utilizing the earlier describedprocedures (WO07137103, WO07137107, WO06113919). Preparation of 29 from28 or 30 from corresponding unsaturated esters may be obtained byMichael-type additions (Green, Tetrahedron Lett., 1989, 30, 4807-4810).Intermediates of formula 30 may be transformed to 29 by Friedel-Craftsacylation reaction (Zhao et al, J. Med. Chem., 2008, 51, 380-383).

Preparation of compounds of 34 from intermediate 33 may be attained byutilizing the procedures described before (WO07137103, WO07137107,WO06044775, WO07016538, WO08099221, and WO09011285). Substituted aminophosphonic acid esters can be made with the procedures that arewell-known in the literature (Chandrasekhar et al, Synlett, 2003, 4,505-506). Monoester 33 can be prepared from corresponding diesters viathe reactions described earlier, from 2 to 3. Such compounds can also bemade in enatiomerically pure form when R¹⁰ and R¹¹ are not equivalent(Ordonez et al, Tetrahedron, 2009, 65, 17-49).

Methods of preparation of compounds of the present invention describedin schemes 2 to 8 delineate the synthesis of phosphorus esters,protected with R′ group. Such R′ group may be selected from alkyl,allyl, aryl or benzyl substituents. These esters may be deprotected tocompounds of Formula I in conditions described for compounds of formula5 from 4 in scheme 1.

BIOLOGICAL EXAMPLES Example A Inhibition of Rat and Human MicrosomalDGAT Activity

The inhibition of DGAT-1 activity can be assessed in intestinalmicrosome preparations by monitoring the incorporation of radiolabeledfatty acyl-CoA into DAG.

Methods: Commercial microsomal preparations containing 60 ug of proteinare incubated in assay buffer [20 uM 1,2-didecanloyl glycerol, 5 uM ¹⁴Cdecanoyl-CoA, 5 mM MgCl₂, 0.4% BSA, 0.1% dimethyl sulfoxide (DMSO), 50mM HEPES-pH 7.5] in the presence of varying concentrations of inhibitorsthat are dispensed from 100% DMSO stock solutions. Final assay volumesare 200 uL. Reactions are carried out for 45 minutes in 96-wellpolystyrene microtiter plates at ambient temperature. Following theambient temperature incubation, assay mixtures are applied to a 96-wellfilter plate (Catalog # MSHVN4510, Millipore Inc.; Billerica, Mass.)under vacuum. The filter plate is pre-equilibrated with 100 uL of 70%ethanol followed by 200 uL of assay buffer. Filters are dried, removedand placed in scintillation vials with 4 mL of scintillation cocktail(Catalog #6013329; PerkinElmer Inc.; Waltham, Mass.). De novo ¹⁴C-TAGformed in the assay and trapped on the filters is quantified with use ofa liquid scintillation counter (Model # LS6500 Beckman Coulter, Inc.;Fullerton, Calif.). The IC₅₀ is defined as the concentration of compoundthat results in a 50% reduction in TAG synthesis.

Results:

TABLE 2 DGAT-1 Inhibition of Compounds of the Present Invention CompoundNumber hDGAT1 IC₅₀* 1 A 2 B 3 A 5 A 6 C 7 C 8 A 9 A 10 A 11 A 12 B 13 A14 A 17 A 18 B 19 A 20 A 21 A 22 B 23 A 24 C 25 B 26 B 30 B 31 B 32 B 33B 34 B *‘A’ represents IC₅₀ value < 10 nM ‘B’ represents IC₅₀ valuebetween 10 and 100 nM ‘C’ represents IC₅₀ value between 100 and 1000 nM

Example B In Vivo Assay for Intestinal Triglyceride Export

The following screen can be used to evaluate the effects of DGAT-1inhibitors on the export of dietary TAGs from the intestine to thecirculation in rodents (male Sprague Dawley rats or C57BL/6 mice).

Methods: Animals (housed 2/cage) are fasted overnight, and dosed (PO)the next day with vehicle (1% Tween-80) or test compound at dosesranging from 0.01 to 30 mg/kg, followed by an oral gavage of olive oil.Blood samples are taken at baseline and at appropriate intervals overthe course of 4 hours. Serum TAG levels are determined using theInfinity triglyceride reagent per the manufacturer's instructions.

Results: Compounds 1, 2, and 5 reduced the AUC_(0-4h) of serum TAGsfollowing oral administration to Sprague Dawley rats at doses in therange of 0.1 to 30 mg/kg. These results confirm inhibition of enterocyteDGAT-1 by the compounds tested.

Example C Determination of Plasma Pharmacokinetics and OralBioavailability in Rats

Pharmacokinetic studies in rats are useful for the identification ofDGAT-1 inhibitors that have low oral bioavailability and show lowsystemic exposure (i.e. low circulating levels in plasma).

Methods: Groups of male Sprague Dawley rats (200-250 g) (n=3/group) wereadministered either an IV bolus (1% Tween-80, pH adjusted to 7, vehicle)or an oral gavage (50% PEG-200 in 1% Tween-80 vehicle) of 5 mg/kg ofeach DGAT-1 inhibitor. Blood (EDTA) was collected by tail nick at 0.5,1, 2, 4, 8, 10-12 and 24 hr post dose. Following centrifugation of theblood to obtain plasma, the samples were analyzed by LC-MS/MS method foractive metabolite. The pharmacokinetic parameters were calculated bynoncompartmental analysis of the plasma concentration-time profile ofthe active metabolite. The oral bioavailability was determined bydividing the dose-normalized plasma AUC value of the active metabolitefollowing oral administration of the DGAT-1 inhibitor by the plasma AUCvalue of the active metabolite after IV bolus administration.

Results: A summary of the key plasma pharmacokinetic parameters of theDGAT-1 inhibitors evaluated is shown in the table below. Compounds ofthe invention that were tested have low oral bioavailability, <10%, andlow systemic exposure as indicated by a Cmax<0.01 ug/mL. In contrast,known DGAT inhibitors X, Y, and Z were found to have high oralbioavailability and high plasma exposure.

TABLE 3 Key Plasma Pharmacokinetic Parameters of DGAT-1 Inhibitors^(1,2)Compound Oral bioavailability, % Cmax, ug/mL X 75 4.81 Y 70 3.33 Z 678.68 1 5.6 0.009 2 1.1 0.005 5 0.9 0.003 ¹LOQ = 0.001 ug/mL ²Compound X,Compound 2 of Birch et al, J. Med. Chem., 2009 (DOI: 10.1021/jm801507v);Compound Y, compound 1 of Birch et al, J. Med. Chem., 2009 (DOI:10.1021/jm801507v); Compound Z, Example 1 of WO07144571.

Example D In Vivo Assay for Effects on Food Intake

The following assay can be used to evaluate the anorectic efficacy ofDGAT-1 inhibitors rodents (male Sprague Dawley rats or C57BL/6 mice).

Methods: Animals (rats housed 1/cage, or mice housed 2/cage) are fastedovernight. The next morning, animals are dosed (PO) with vehicle (1%Tween-80) or test compound (doses ranging from 0.1 to 30 mg/kg). Food isthen presented immediately following vehicle or compound administration.Food is weighed manually at 1-3 hour intervals to determine anyinhibitory effects on food intake.

Results: Compounds of the invention reduced food intake significantlyfollowing oral administration at doses ranging from 0.1 to 30 mg/kg.

Example E In Vivo Assay for Gut Hormone Secretion

The following procedure may be used to evaluate the effect of testcompounds on gut hormone (e.g., PYY, GLP1, CCK, etc) secretion inrodents.

Methods: Animals (male Sprague Dawley rats or C57BL/6 mice) in a fed orfasted state are orally gavaged with a nutrient load (oil, carbohydrate,and/or protein) immediately following administration of vehicle or testcompound (doses ranging from 0.01-30 mg/kg). Baseline and temporalbleeds are taken to determine serum concentrations of gut hormones ofinterest using commercially available ELISA/RIA kits as per themanufacturer's instructions.

Results: Administration of compounds of the invention to rodents atdoses ranging from 0.1 to 30 mg/kg results in an increase in one or moregut hormones in plasma.

Example F In Vivo Assay for Weight Loss and Reduction in Adiposity

The effects of DGAT-1 inhibitors on body weight and adiposity can beassessed in standard animal models of obesity such as the high-fat fedmouse or rat.

Methods: Mice (diet-induced obese male, C57BL/6) that have been fed ahigh fat diet for >12 weeks are sham-dosed bid with water untilacclimated to dosing (as determined by stable or steadily increasingbody weights). Thereafter, vehicle (1% Tween-80) or test compound (dosesranging from 0.3-30 mg/kg) are dosed (PO, bid) daily for up to 28 days.Food intake and body weights are monitored daily to determine anorecticand weight loss efficacy. At the end of the study, lean and fat mass canbe assessed by NMR.

Results: Compounds of the invention significantly reduce body weight andadiposity after daily administration at doses ranging from 0.1 to 30mg/kg for several days to several weeks.

Example G In Vivo Assay for Determination of Insulin Sensitivity

The insulin tolerance test was developed to evaluate insulin sensitivityin humans and in animal models (Monzillo et al, Nutrition Reviews, 2003,61(12):397-412; Bonora et al, J Clin Endocrinol Metab. 1989, 68:374-378;Bergman, Endocrine Reviews, 1985, 6:45-86). Diet-induced obese (DIO)mouse or rat models can become insulin resistant with prolonged high fatfeeding and have been used to test for improved insulin sensitivity withinsulin sensitizing drugs such as glitazones (Guerre-Millo M et al, JBC2000 275: 16638-42; Schupp M et al; Diabetes, 2005 54: 3442-52;Arulmozhi DK, 2008, 60(9):1167-73) and in genetically manipulated mice(Fujii N. et al, Diabetes, 2008, 57:2958-66; Funato H et al, CellMetabolism, 2009, 9(1):64-76).

Methods: DIO mice or rats that were subchronically or acutely treatedwith vehicle or test compound (doses ranging from 0.1-30 mg/kg) arefasted for up to 14 hours and are injected (i.p., 1 U/kg) with Humalog(a fast-acting insulin analog). The temporal profile of blood glucoselevels is monitored using One-Touch glucometers for up to 3 hourspost-injection.

Results: Compounds of the invention improve insulin sensitivity afterone or multiple weeks of dosing when administered at doses ranging from0.1 to 30 mg/kg/day to DIO mice or rats. This is evident from the lowerglucose levels following insulin administration in the treated versusthe control animals.

REFERENCES

-   Chen, H. C., Stone, S. J., Zhou, P., Buhman, K. K., Farese, R. V.    Jr. (2002) “Dissociation of obesity and impaired glucose disposal in    mice overexpressing acyl coenzyme a:diacylglycerol acyltransferase 1    in white adipose tissue” Diabetes 51(11):3189-95.-   Chen, H. C., Farese, R. V. Jr. (2005) “Inhibition of triglyceride    synthesis as a treatment strategy for obesity: lessons from    DGAT1-deficient mice” Arterioscler Thromb Vasc Biol 25(3):482-6.-   Hill, J. O., Melanson, E. L., Wyatt, H. T. (2000) “Dietary fat    intake and regulation of energy balance: implications for obesity” J    Nutr. 30 (2S Suppl):2845-2885.-   Shi, Y., Burn, P. (2004) “Lipid metabolic enzymes: emerging drug    targets for the treatment of obesity” Nat Rev Drug Discov 3    (8):695-710.-   Smith, S. J., Cases, S., Jensen, D. R., Chen, H. C., Sande, E., Tow,    B., Sanan, D. A., Raber, J., Eckel, R. H., Farese, R. V. Jr. (2000)    “Obesity resistance and multiple mechanisms of triglyceride    synthesis in mice lacking Dgat” Nat Genet 25(1):87-90.-   Stone, S. J., Myers, H. M., Watkins, S. M., Brown, B. E.,    Feingold, K. R., Elias, P. M., Farese, R. V. Jr (2004) “Lipopenia    and skin barrier abnormalities in DGAT2-deficient mice” J Biol Chem.    19; 279(12): 11767-76.-   Van Herpen, N. A., Schrauwen-Hinderling, V. B. (2008) “Lipid    accumulation in non-adipose tissue and lipotoxicity” Physiol Behav    94(2):231-41.-   Yamazaki, T., Sasaki, E., Kakinuma, C., Yano, T., Miura, S.,    Ezaki, O. (2005) “Increased very low density lipoprotein secretion    and gonadal fat mass in mice overexpressing liver DGAT1” J Biol    Chem. 280(22):21506-14.-   Yen, C. L., Monetti, M., Burri, B. J., Farese, R. V. Jr. (2005) “The    triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis    of diacylglycerols, waxes, and retinyl esters” J Lipid Res    46(7):1502-11.-   Yen, C. L., Stone, S. J., Koliwad, S., Harris, C., Farese, R. V.    Jr. (2008) “Thematic review series: glycerolipids. DGAT enzymes and    triacylglycerol biosynthesis” J Lipid Res 49(11):2283-301.-   Zhao, G., Souers, A. J., Voorbach, M., Falls, H. D., Droz, B.,    Brodjian, S., Lau, Y. Y., Iyengar, R. R., Gao, J., Judd, A. S.,    Wagaw, S. H., Ravn, M. M., Engstrom, K. M., Lynch, J. K.,    Mulhern, M. M., Freeman, J., Dayton, B. D., Wang, X., Grihalde, N.,    Fry, D., Beno, D. W., Marsh, K. C., Su, Z., Diaz, G. J., Collins, C.    A., Sham, H., Reilly, R. M., Brune, M. E., Kym, P. R. (2008)    “Validation of diacyl glycerolacyltransferase I as a novel target    for the treatment of obesity and dyslipidemia using a potent and    selective small molecule inhibitor” J Med Chem 51(3):380-3.

We claim:
 1. A compound of Formula (I), pharmaceutically acceptablesalts or stereoisomers thereof,Q-G¹-G²-G³-G⁴-Z  Formula (I) wherein Q is

wherein R⁶ is an optionally substituted aryl or optionally substitutedheteroaryl group, wherein the optional substituents are one or moregroups selected from a group H, (C₁-C₄)alkyl, halo, halo(C₁-C₄)alkyl,cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, —C(O)_(x)R^(a), —OR^(a)—S(O)_(x)R^(a), —NR^(a)R^(b), —C(O)NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)CO NR^(a)R^(b), —S(O)₂ NR^(a)R^(b) or —NR^(a)S(O)₂NR^(a)R^(b)where x is an integer of 1 or 2; and T is N, CH or CMe; G¹ and G³ areindependently selected from the group consisting ofcyclo(C₃-C₈)alkylene, heterocyclo(C₃-C₈)alkylene, arylene andheteroarylene, optionally substituted with one or two groupsindependently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkoxy, cyano, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy,(C₁-C₄)perfluoroalkyl; —N(R^(a) R^(b)), —N(R^(a))—C(O)(R^(a)),—C(O)N(R^(a))₂, —S(O)₂N(R^(a))₂, —S(O)₂(R^(b)), —C(O)(R^(a)), whereinR^(a) and R^(b) are independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, fluoro(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, aryl, heteroaryl and aryl(C₁-C₄)alkyl; G² is selectedfrom the group consisting of a bond, (C₁-C₄)alkylene, (C₂-C₄)alkenylene,O, N(R^(a))C(O), S and S(O)₂, wherein R^(a) is selected from the groupconsisting of H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,fluoro(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl, heteroaryl and aryl(C₁-C₄)alkyl; G⁴ is X—Y—; wherein X is selected from null, O, NH, CO, CHOH,S or S(O)₂; and Y is selected from (C₁-C₄)alkylene, C₃-C₈-cycloalkyleneor heterocycloalkylene, —CH(R⁹)C(R¹⁰R¹¹)— or —N(R⁹)C(R¹⁰R¹¹)—; wherein:R¹⁰ and R¹¹ are both hydrogen, and R⁹ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₂-C₆)alkenyl, phenoxy-(C₂-C₆)alkyl,1-methyl-1H-indol-3-yl, bis[(C₁-C₆)alkyl]amino-(C₂-C₆)alkyl,1-piperidinyl-(C₂-C₆)alkyl, 1-pyrrolidinyl-(C₂-C₆)alkyl, or1-morpholinyl-(C₂-C₆) alkyl; or R¹⁰ and R¹¹ are both hydrogen and R⁹ isR¹²(CH₂)_(m), where m is 0 to 3, and R¹² is phenyl optionallysubstituted with one or more halogen, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, trifluoromethyl or cyano; or R¹⁰ and R¹¹ are bothhydrogen and R⁹ is R¹²(CH₂)_(m), where m is 0 to 3, and R¹² is2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, each of which is optionallysubstituted with halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethylor cyano; or R⁹ is hydrogen, and R¹⁰ and R¹¹ together with the carbonatom to which they are attached, form a three to five-membered ring,with 0 to 2 heteroatoms independently selected from O, S or N; or R¹⁰ ishydrogen, and R⁹ and R¹¹ together with the two carbon atoms to whichthey are attached, form a three- to six-membered ring with 0 to 2heteroatoms independently selected from O, S or N;

Z is X¹ and X² are independently selected from null,(C(R^(a)R^(b)))_(n), O, NR^(a), S or CO and n is 0 or 1; W is selectedfrom H, (C₁-C₆)alkyl, aryl, heteroaryl or (C₃-C₈)cycloalkyl; whereineach of the (C₁-C₆)alkyl, aryl, heteroaryl and cycloalkyl isindependently substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from the group consisting of (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, —CN, halogen, ethylenedioxy,methylenedioxy, haloalkyl, —OR^(a), —O—C(O)(R^(a)), —S(R^(a)),—S(O)(R^(b)), —S(O)₂(R^(b)), —C(O)(R^(a)), —C(O)(OR^(a)), —N(R^(a))₂,—N(R^(a))—C(O)(R^(a)), —C(O)N(R^(a))₂, —S(O)₂N(R^(a))₂,—(CR^(a)R^(b))_(t)OR^(a), —(CR^(a)R^(b))_(t)—O—C(O)(R^(a)),—(CR^(a)R^(b))_(t)S(R^(a)), —(CR^(a)R^(b))_(t)S(O)(R^(b)),—(CR^(a)R^(b))_(t)S(O)₂(R^(b)), —(CR^(a)R^(a))_(t)C(O)(R^(a)),—(CR^(a)R^(b))_(t)C(O)(OR^(a)), —(CR^(a)R^(b))_(t)N(R^(a) R^(b))—(CR^(a)R^(b))_(t)N(R^(a))—C(O)(R^(a)), —(CR^(a)R^(b))_(t)C(O)N(R^(a))₂,—(CR^(a)R^(a))_(t)S(O)₂N(R^(a))₂ and —(CR^(a)R^(b))_(t)R^(a),—(CR^(a)R^(b))_(t)P(O)(OH)₂, and —(CR^(a)R^(b))_(t)P(O)(OH)(R^(a)),wherein t is an integer of 1, 2, 3, or 4 and R^(a) and R^(b) areindependently selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, fluoro(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,aryl, heteroaryl and aryl(C₁-C₄)alkyl; X¹ and X² may be combined to forma 5-, 6- or 7-membered ring having from 0 to 3 heteroatoms selected fromthe group consisting of NR^(a), O and S; or X¹ or X² may be combinedwith W to form a 5-, 6-or 7-membered fused ring having from 0 to 3heteroatoms selected from the group consisting of NR^(a), O and S; andwith a proviso that when X² is O, then X¹ is not (C(R^(a)R^(b)))_(n). 2.The compound according to claim 1, wherein said compound is: CompoundNumber Structure  5


3. A pharmaceutically acceptable composition comprising apharmaceutically acceptable carrier, vehicle or diluent and a compoundaccording to claim
 1. 4. The composition according to claim 3, whereinsaid compound is: Compound Number Structure  5